Drug Use Evaluation of Tamoxifen Focusing on Off-Label Use in a Managed Care Population in Israel

BACKGROUND: Policy development to manage new off-label uses of medications is an issue relevant to health policy stakeholders internationally. Retrospective drug utilization analyses may be useful to identify practice trends in the use of drugs for unapproved (off-label) uses. Since drug use evaluations (DUE) are generally performed for expensive medications or when safety concerns warrant increased scrutiny, patterns of off-label use of inexpensive drugs will probably be undetected. Tamoxifen citrate, an estrogen receptor antagonist, is indicated in Israel exclusively for palliative [sic: meaning adjuvant] treatment of breast cancer. This DUE was motivated by observations that tamoxifen may be used off-label for indications without evidence of safety or efficacy. OBJECTIVES: To assess the extent of off-label prescribing of tamoxifen and ascertain what evidence is available supporting the use of the drug for the off-label indications observed. METHODS: A retrospective DUE of tamoxifen was performed for the 12 months of calendar year 2008 in a 650,000-member HMO in Israel for patients who received at least 1 prescription for tamoxifen. All patients for whom tamoxifen was dispensed in 2008 were identified from pharmacy claims data. The HMOs electronic patient record (EPR) was subsequently queried to identify the diagnoses of patients who received tamoxifen and exclude those patients who had a diagnosis code (ICD-9-CM 174.x or 175.x) for breast cancer. An EPR chart review was also performed to identify and exclude patients who had a diagnosis or treatment of breast cancer that was recorded in free text. For the patients who did not have a diagnosis code or free-text description of breast cancer, the recorded off-label diagnoses and ICD-9-CM codes in the EPR during the visit when tamoxifen was first prescribed were tabulated. A literature search was conducted to collect information supporting the use of tamoxifen for the observed offlabel indications. We defined the use as "supported" if studies were found in PubMed, Cochrane database, or Micromedex that supported the clinical decision to use the drug for the off-label indication. RESULTS: 877 patients were treated with tamoxifen in 2008 of whom 826 (94.2%) had a diagnosis of breast cancer, and 51 patients (5.8%) received the drug from 41 physicians in 7 medical specialty categories for 25 different off-label diagnoses. Of these 25 diagnoses, 33 patients (64.7% of 51 patients with off-label use) received tamoxifen for 8 diagnoses that were associated with some evidence to support their off-label use. Malignant neoplasm of ovary (n = 13) and female infertility (n = 13) were the most commonly recorded indications with some evidence to support off-label use. Of the 13 women treated for infertility, 9 (69.2%) had been treated with clomiphene citrate prior to being treated with tamoxifen, suggesting that some physicians may be experimenting with tamoxifen as second-line treatment. CONCLUSIONS: Tamoxifen was found to be used off-label in only 5.8% of the patients who received the drug in 2008 in this HMO, and only 18 patients (2.1%) received tamoxifen for a diagnosis that did not have some supporting evidence of efficacy. Since off-label prescribing of tamoxifen was found to be relatively rare, this HMO did not impose a prior authorization requirement for this drug and instead added an edit in the EPR to block off-label prescribing by requiring the physician to register a diagnosis of breast cancer.

METhODS: a retrospective DUE of tamoxifen was performed for the 12 months of calendar year 2008 in a 650,000-member hMO in Israel for patients who received at least 1 prescription for tamoxifen. all patients for whom tamoxifen was dispensed in 2008 were identified from pharmacy claims data. The hMO's electronic patient record (EPr) was subsequently queried to identify the diagnoses of patients who received tamoxifen and exclude those patients who had a diagnosis code (ICD-9-CM 174.x or 175.x) for breast cancer. an EPr chart review was also performed to identify and exclude patients who had a diagnosis or treatment of breast cancer that was recorded in free text. For the patients who did not have a diagnosis code or free-text description of breast cancer, the recorded off-label diagnoses and ICD-9-CM codes in the EPr during the visit when tamoxifen was first prescribed were tabulated. a literature search was conducted to collect information supporting the use of tamoxifen for the observed offlabel indications. We defined the use as "supported" if studies were found in PubMed, Cochrane database, or Micromedex that supported the clinical decision to use the drug for the off-label indication. rESULTS: 877 patients were treated with tamoxifen in 2008 of whom 826 (94.2%) had a diagnosis of breast cancer, and 51 patients (5.8%) received the drug from 41 physicians in 7 medical specialty categories for 25 different off-label diagnoses. Of these 25 diagnoses, 33 patients (64.7% of 51 patients with off-label use) received tamoxifen for 8 diagnoses that were associated with some evidence to support their off-label use. Malignant neoplasm of ovary (n = 13) and female infertility (n = 13) were the most commonly recorded indications with some evidence to support off-label use. Of the 13 women treated for infertility, 9 (69.2%) had been treated with clomiphene citrate prior to being treated with tamoxifen, suggesting that some physicians may be experimenting with tamoxifen as second-line treatment.
COnCLUSIOnS: Tamoxifen was found to be used off-label in only 5.8% of the patients who received the drug in 2008 in this hMO, and only 18 patients (2.1%) received tamoxifen for a diagnosis that did not have some supporting evidence of efficacy. Since off-label prescribing of tamoxifen was found to be relatively rare, this hMO did not impose a prior authorization requirement for this drug and instead added an edit in the EPr to block off-label prescribing by requiring the physician to register a diagnosis of breast cancer.

B R I E F C O M M U N I C AT I O N
• Although tamoxifen citrate is indicated in Israel exclusively for palliative [sic: adjuvant] treatment of breast cancer, it is being prescribed off-label for other conditions including second-line treatment for anovulatory women refractory to clomiphene citrate to treat infertility, for which there is some evidence for efficacy. • DUE analyses of off-label prescribing may be used to better define the need for utilization management interventions designed to ensure appropriate use including avoidance of risks to patient safety associated with prescribing of drugs for indications that do not have sufficient evidence for safety or efficacy.
What this study adds P olicy formulation and implementation for innovative off-label use of medications are issues relevant to health policy stakeholders internationally. Although off-label medication use in the United States is common and permitted by the U.S. Food and Drug Administration (FDA), 1,2 drugs may not be prescribed in Israel for unapproved indications unless Ministry of Health (MOH) authorization is granted (Table 1). Despite this regulation, unapproved off-label use of drugs will not be prospectively identified and regulated unless a prior authorization (PA) requirement is imposed by the health maintenance organizations (HMOs) that provide coverage.
drug. The objectives of this study were to quantify the extent of off-label prescribing of tamoxifen and to ascertain what evidence is available to support use of the drug for the off-label indications observed.

■■ Methods
A retrospective DUE of tamoxifen utilization in the LHF of Israel during the 12 months of 2008 was conducted to identify the patients without a recorded diagnosis of breast cancer. First, all patients for whom tamoxifen was dispensed in this period were identified from pharmacy claims data. A database query of the HMO's electronic patient records (EPR) was conducted to identify and exclude the patients who had a history of breast cancer ( An EPR chart review was then conducted by a clinical pharmacist (Blackman) for all patients receiving tamoxifen without a recorded diagnosis code for breast cancer in the EPR. The purpose of the chart review was to examine free text fields to identify and exclude patients who had a diagnosis or treatment of breast cancer that was not identified with a diagnosis code. For the remaining patients receiving tamoxifen without a recorded diagnosis of breast cancer, the diagnoses entered in their EPR during the visit when tamoxifen was first prescribed were recorded and evaluated. The proportion of patients receiving tamoxifen for off-label indications was then calculated.
A literature search was conducted to collect any information that has been reported supporting the use of tamoxifen for the observed off-label indications. We defined the use as "supported" if studies were found in PubMed, the Cochrane Database of Systematic Reviews, or Micromedex (references cited in Table 2) that to any degree supported the clinical decision to use the drug off-label for the recorded diagnoses. The number of patients receiving tamoxifen for each "unsupported" indication was determined.

■■ Results
During the study period, 877 patients (95.9% female, n = 841) were treated with tamoxifen, 51 (5.8%) of whom received tamoxifen for 25 different off-label diagnoses by 41 physicians in 7 medical specialty categories: family practice, oncology, pediatrics, gynecology, internal medicine, neurology, and nonspecialists (e.g., practicing physicians who have not completed training in a subspecialty). All of the prescriptions were from physicians in office-based practices or HMO clinics, and some unknown portion of these prescriptions may have resulted from recommendations from hospital-Since many drugs prescribed off-label are inexpensive, HMOs will most likely not have a financial incentive to impose a PA requirement for these medications, preferring to allocate the resources required for PA to manage the use of more expensive treatments. 3 Accordingly, retrospective drug use evaluation (DUE) is the only method for medical managers to identify and analyze patterns of off-label prescribing of these drugs. Since DUEs are generally restricted to expensive medications or when safety considerations warrant increased scrutiny, patterns in off-label use of inexpensive drugs will probably go undetected.
The Leumit Health Fund (LHF) is a managed care organization (MCO) that provides medical coverage to approximately 650,000 members throughout Israel. LHF is 1 of the 4 HMOs in Israel that provides health coverage under Israel's National Health Insurance Law. 4 LHF provides coverage to a relatively young population, with 25% of its members younger than age 13 years, 50% younger than age 28 years, 75% younger than age 47 years, and 8.2% aged 65 years or older; 50.2% of LHF members are female.
Tamoxifen citrate, an estrogen receptor antagonist, is indicated in Israel only for the adjuvant treatment of breast cancer. 5 Recently, a number of cases came to our attention at LHF in which tamoxifen was prescribed for indications other than breast cancer. Because the authors were unaware of any recommendations for off-label use of this drug, this observed prescribing seemed unusual, raising a number of questions. First, the extent of off-label prescribing of tamoxifen in LHF was not known and seemed to warrant evaluation. Additionally, information from the published literature was desired to determine whether the off-label prescribing that would be observed represented accepted use or new use of an old medication that was not supported or possibly an experimental use of the drug. Of particular concern was the possible prescribing of the drug for diseases in which better alternatives exist that have an established safety profile for the indication. We therefore decided to allocate MCO resources to analyze the prescribing of tamoxifen to determine whether there may be a case for action to implement administrative interventions to regulate the use of this

Approved Indications for Tamoxifen in the United States a and Israel b
Metastatic breast cancer Adjuvant treatment of breast cancer b Ductal carcinoma in situ (DCIS) Reduction in breast cancer incidence in high risk women c a Nolvadex (tamoxifen citrate) prescribing information. 10 b Tamoxifen citrate is approved in Israel only for palliative (adjuvant) treatment of breast cancer. 5,10 c This indication is associated with a black-box warning on the label. 10 pected (e.g., mammography screening in suspected cases of breast cancer where the physician started tamoxifen therapy before there was a conclusive diagnosis) were re-evaluated for text or other indications to rule out erroneous data entry.
Of the 25 off-label diagnosis categories, 8 met the study criteria to be defined as "supported." Of the 51 patients identified based physicians. Prescriptions originated from all 4 regions of LHF throughout Israel. The records of the 826 patients with a diagnosis of breast cancer were subsequently reviewed to identify any off-label indications, and none were found to have an off-label diagnosis of any of the off-label uses observed in this study. Cases in which miscoding was sus- with off-label diagnoses, 33 (64.7%) were treated for diagnoses defined as "supported" according to the criteria used in this study. Information supporting use was found in Micromedex and the Cochrane Database; PubMed searches using "tamoxifen" as a search term did not add any supplementary information. The 2 most commonly recorded off-label diagnoses in this DUE were malignant neoplasm of ovary (n = 13) and female infertility (n = 13), both defined as "supported" ( Table  2). Of the 13 women treated with tamoxifen for infertility, 9 (69.2%) had been previously treated with clomiphene citrate. The strength of the recommendations in Micromedex did not exceed Class IIb (defined as "recommended in some cases" without further elaboration) for any of the observed diagnoses. In Israel, MOH authorization is required for individual patients before prescribing tamoxifen for indications other than breast cancer, but as the results of this study indicate, this regulation is not adhered to closely.

Ovarian Cancer
There is some evidence from observational studies that tamoxifen may be effective in some patients with relapsed ovarian cancer. A 2001 Cochrane systematic review of 2 randomized controlled trials (RCTs) and 11 observational studies found that 60 of 623 patients (9.6%) with relapsed ovarian cancer had an objective response to tamoxifen. 6 However, the Cochrane review found no reliable data from RCTs, and this off-label indication is not listed in Micromedex. The Cochrane reviewers also concluded that "there were not enough data to assess duration of response, survival, or the palliative effect of tamoxifen on symptom control or quality of life." 6

Female Infertility
The efficacy of tamoxifen as a suitable alternative agent to clomiphene citrate in the management of anovulatory infertility has been studied in 2 RCTs. 7,8 Although the findings of these 2 RCTs provide evidence supporting the effectiveness of clomiphene citrate for first-line treatment, the 2 drugs appear to be equally effective. The authors of the Cochrane systematic review concluded that "no evidence of a difference in effect was found between clomiphene and tamoxifen." 9

■■ Discussion
The findings of this analysis of the off-label prescribing of a drug with only 1 approved indication in Israel exemplify 2 markedly distinct scenarios of off-label drug prescribing in the outpatient setting. The evidence base and the strength of recommendation to support use of tamoxifen in the 2 most prevalent off-label diagnoses observed in this patient population vary for ovarian cancer versus female infertility. For the off-label use for ovarian cancer, the evidence base is weak, whereas the evidence base for off-label use in female infertility is stronger. While the use of tamoxifen in ovarian cancer may help some women suffering from a life-threatening illness, clinicians and policymakers lack data from RCTs to support decisions for this use.
In second-round review, we verified that these ovarian cancer patients had or were being treated with standard therapies and that physicians were not experimenting with tamoxifen as first-line treatment in these women. Ultimately, we found no concern that tamoxifen was being used when better alternatives are available, and there was no need for increased vigilance in monitoring the use of the drug from a clinical perspective. However, since MOH regulations do not permit off-label use of drugs without prior MOH authorization, it was necessary for LHF to block off-label prescribing of tamoxifen and set policy concerning which requests would be submitted to the MOH.
Unlike treatment of ovarian cancer, where there is no evidence from RCTs of the efficacy of tamoxifen, the use of tamoxifen in anovulatory women has been investigated in RCTs in which there was no difference in efficacy between tamoxifen and clomiphene. The findings of our DUE suggest that some physicians are prescribing the drug for second-line treatment for women not responding to clomiphene citrate. Our literature search did not yield any studies that evaluated the safety and efficacy of tamoxifen as second-line treatment of anovulatory women or any suggestions to treat women refractory to clomiphene citrate with tamoxifen.
Tamoxifen and clomiphene are nonsteroidal selective estrogen receptor modulators, and the available evidence suggests that there is no difference in their efficacy in inducing ovulation. Although not studied specifically as second-line therapy after failure to induce ovulation with clomiphene, it seems reasonable that some physicians may use tamoxifen off-label for this indication. It is in this context that the findings of this study are interesting. This DUE appears to have uncovered a second-line treatment modality that physicians are experimenting with before clinical trials or observational studies have evaluated its efficacy in second-line treatment. Since tamoxifen is a relatively inexpensive drug, this experimentation may generate a new cost-effective treatment that will help some infertile women. The findings of this exploratory DUE may therefore suggest that studies of this kind may be beneficial in identifying treatment modalities worthy of being evaluated in comparative effectiveness research.
We believe that this study is of interest in part because the findings suggest that DUEs can be used to identify new uses of inexpensive drugs. This process may be valuable in identifying alternatives to more expensive drugs or in adding to our arsenal of effective treatments where alternatives do not exist. This may be of particular value for conditions in which pharmaceutical companies do not have an economic incentive to develop new products or when long development periods would leave patients without effective treatment for long periods of time.
However, since funding for research with generic drugs is not available, RCTs may be impractical, and observational studies on larger patient populations may be necessary to evaluate alternate treatments when conducting comparative effectiveness research. However, the small sample of cases evaluated in this study was insufficient to inform clinical practice guideline formulation in this MCO, and the results did not support a petition to the MOH to revise the list of labeled indications for tamoxifen.
Issues inherent in the conduct of DUE studies in MCOs include the administrative costs for conducting these analyses and the managerial and/or clinical justification for expending MCO resources on this type of evaluation. LHF implemented an EPR system in 1999 that provides managers with data on drugs prescribed and dispensed, and these data can be easily queried and analyzed using spreadsheet programs without the need for trained programmers or sophisticated data retrieval processes. These data capabilities have enabled LHF clinical pharmacists to perform relatively detailed DUE analyses with readily available data and user-friendly software. Additionally, these pharmacists have access to individual patient records enabling them to both validate data and read free text. With these tools, pharmacist-investigators can conduct all stages of these analyses for decision makers without the need to allocate additional resources, such as physicians or information technology specialists. This study was performed with the expenditure of an estimated 20 hours of pharmacist time plus 10 physician-hours. Therefore, the methods used in this study have the additional value of providing a template for conducting DUE analyses for future decision making regarding drug use policy.
Since off-label prescribing of tamoxifen was found to be relatively rare, LHF did not impose a PA requirement for this drug. Instead, an edit was added to the EPR system that blocked off-label prescribing by requiring the physician to have entered a diagnosis of breast cancer before a prescription for tamoxifen could be dispensed.

Limitations
This DUE was limited to the data and information contained in EPRs.

■■ Conclusions
The rate of off-label use of tamoxifen in this managed care population was about 6%. Although the off-label use was generally not evidence based, it was rare and not an apparent threat to patient safety. Retrospective DUEs of off-label prescribing might be useful for health plans to identify target drugs for utilization management and to suggest possible new uses of old, inexpensive drugs that might be the subject of comparative effectiveness research.

DISCLOSURES
There was no external funding for this research. The findings of this study were presented at The Israel National Institute for Health Policy and Health Services Research Fourth International Jerusalem Conference on Health Policy, Jerusalem, Israel, December 7-10, 2009.
Kahan and Waitman designed the study, and Kahan and Blackman collected the data. All authors contributed to data interpretation. Kahan wrote and revised the manuscript with the assistance of the other authors.